Int. J. Radiation Oncology Biol. Phys., Vol. 3 I, No. 5, pp.
I34 I - 1346, 1995
Pergamon
0360-3016(95)00060-7
l Editorial
TOXICITY CRITERIA OF THE RADIATION THERAPY ONCOLOGY
(RTOG) AND THE EUROPEAN ORGANIZATION FOR RESEARCH
TREATMENT OF CANCER (EORTC)
JAMES D. Cox, M.D.,’ JOANN STETZ, B.S.’
‘University of Texas M.D. AndersonCancerCenter, Houston,Texas and ‘Radiation Therapy Oncology Group, Philadelphia,PA
The therapeutic useof ionizing radiations is predicated on
sparing normal tissue effects while attempting to achieve
lethal effects on tumor cells. From quite early in the his-
tory of radiation therapy, it was apparent that there were
striking differences in effects in the panoply of normal
tissues. Although there was early appreciation of some
late effects in normal tissues,often not predicted by acute
reactions, only in recent years has there been full docu-
mentation of the slow and progressive increasein severity
of late damage. Pathophysiological mechanismsof acute
and late radiation effects are better understood today (2),
but interactions of other modalities with radiation therapy
require constant monitoring to recognize and mitigate un-
toward sequelae.
The work of Stone (3) is a classic example of unantici-
pated late effects, which resulted from irradiation with
‘fast neutrons. Acute reactions were moderate and tolera-
ble, but the late sequelae were so marked that there was
little interest in pursuing therapy with fast neutrons for
nearly three decades.
The Late Morbidity Scoring Criteria were developed
asa joint effort between physicians with renewed interests
in fast neutron therapy and Radiation Therapy Oncology
Group (RTOG) staff. In the late 1970s the Neutron/Parti-
cle Committee was one of several modality committees
of the RTOG. Recognizing the results of Stone, this com-
mittee, led by Lawrence Davis worked with RTOG staff
to establish criteria and scoring for possible late effects
from fast neutron radiation therapy. Investigators from
the European Organization for Research and Treatment of
Cancer (EORTC), led by William Duncan of the Western
General Hospital of Edinburgh, wished to have common
toxicity criteria in anticipation of joint studies.
Reprint Requeststo: Dr. JamesD. Cox at University of Texas
M.D. AndersonCancerCenter, Box 3 12, I5 1.5HolcombeBou-
levard, Houston,TX 77030.
Acknowledgements-Supported by Public Health Service
Grants CA-21661 and CA-321 15 from the National Cancer In-
1341
Copyright Q 1995 Elsevier Science Ltd
Printed in the USA. All rights reserved
0360.3016/95 $9.50 + .OO
GROUP
AND
AND THOMAS F. PAJAK, PH.D.~
RTOG Protocol 7929, an international registry of pa-
tients treated with heavy particles, was started in 1980.
At the annual meetings of the international participants
in particle studies, there were attempts to monitor interob-
server variations in scoring effects in normal tissues and
to seek consistency in reporting toxicity, but no publica-
tions document these efforts. The first prospective trial to
use the Late Morbidity Scoring Criteria was RTOG Proto-
col 8001, a study of fast neutron therapy for malignant
tumors arising in salivary glands.
Although the RTOG began to use these criteria in re-
porting toxicity in patients enrolled in all studies from
198 1 (beginning with RTOG Protocol 8 115), the criteria
only became a published part of protocols in 1983. At
that time, statistical methods began to be used, which
presentedtime-adjusted estimatesof late effects, the ratio-
nale for which was described by Cox (1). It is now consid-
ered standard to represent cumulative probabilities of late
effects with methods similar to those for estimating local
control and survival.
The Acute Radiation Morbidity Scoring Criteria were
developed in 1985 as complimentary to the Late Effects
Scoring Criteria. The National Cancer Institute promul-
gated standard toxicity criteria in 1990, but late effects
were not considered. An abbreviated version of the
RTOG/EORTC toxicity criteria was published by Win-
chester and Cox in 1992 as part of the Standard for Breast
Conservation Treatment.
The current RTOG Acute Radiation Morbidity Scoring
Criteria are presented in Table 1. The RTOG/EORTC
Late Radiation Morbidity Scoring Scheme is detailed in
Table 2. In both tables, 0 means an absence of radiation
effects and 5 means the effects led to death. The severity
stitute, National Institutes of Health, Departmentof Health and
HumanServices.
Accepted for publication 30 January 1995.
 Table 1. RTOG acute radiation morbiditv scoring criteria

Organ Tissue WI [II PI [31 141

Skin No change over Follicular, faint or dull erythema/ Tender or bright erythema, Confluent, moist desquamation Ulceration, hemorrhage,
baseline epilation/dry desquamation/ patchy moist other than skin folds, pitting necrosis
decreased sweating desquamation/moderate edema
edema
Mucous membrane No change over Injection/may experience mild Patchy mucositis that may Confluent fibrinous mucositis/ Ulceration, hemorrhage or
baseline pain not requiring analgesic produce an inflammatory may include severe pain necrosis
serosanguinous discharge/ requiring narcotic
may experience moderate
pain requiring analgesia
Eye No change Mild conjunctivitis with or without Moderate conjunctivitis Severe keratitis with cornea1 Loss of vision (unilateral
scleral injection/increased with or without keratitis ulceration/objective decrease or bilateral)
tearing requiring steroids &/or in visual acuity or in visual
antibiotics/dry eye fields/acute glaucoma/
requiring artificial tears/ panopthalmitis
iritis with photophobia
Ear No change over Mild external otitis with erythema, Moderate external otitis Severe external otitis with Deafness
baseline pruritis, secondary to dry requiring topical discharge or moist
desquamation not requiring medication/serous otitis desquamation/symptomatic
medication. Audiogram medius/hypoacusis on hypoacusisltinnitus, not drug
unchanged from baseline testing only related
Salivary gland No change over Mild mouth dryness/slightly Moderate to complete - Acute salivary gland
baseline thickened saliva/may have dryness/thick, sticky necrosis
slightly altered taste such as saliva/markedly altered
metallic taste/these changes not taste
reflected in alteration in baseline
feeding behavior, such as
increased use of liquids with
meals
Pharynx & esophagus No change over Mild dysphagia or odynophagial Moderate dysphagia or Severe dysphagia or Complete obstruction,
baseline may require topical anesthetic odynophagialmay require odynophagia with ulceration, perforation,
or non-narcotic analgesics/may narcotic analgesics/may dehydration or weight loss > fistula
require soft diet require puree or liquid 15% from pretreatment
diet baseline) requiring N-G
feeding tube, iv. fluids or
hyperalimentation
Larynx No change over Mild or intermittent hoarseness/ Persistent hoarseness but Whispered speech, throat pain Marked dyspnea, stridor or
baseline cough not requiring antitussive/ able to vocalize/referred or referred ear pain requiring hemoptysis with
erythema of mucosa ear pain, sore throat, narcotic/confluent fibrinous tracheostomy or
patchy fibrinous exudate exudate, marked arytenoid intubation necessary
or mild arytenoid edema edema
not requiring narcotic/
cough requiring
antitussive
Upper G.I. No change Anorexia with < =5% weight loss Anorexia with < =15% Anorexia with > 15% wt loss Ileus, subacute or acute
from pretreatment baseline/ weight loss from from pretreatment baseline or obstruction, perforation,
nausea not requiring pretreatment baseline/ requiring N-G tube or GI bleeding requiring
antiemeticslabdominal nausea &/or vomiting parenteral support. Nausea &I transfusion/abdominal
discomfort not requiring requiring antiemetics/ or vomiting requiring tube or pain requiring tube
parasympatholytic drugs or abdominal pain requiring parenteral support/abdominal decompression or bowel
analgesics analgesics pain, severe despite diversion
medicatiotiematemesis or
 melena/abdominal distention
(flat plate radiograph
demonstrates distended bowel
loops)
Lower G.I. including pelvis No change Increased frequency or change in Diarrhea requiring Diarrhea requiring parenteral Acute or subacute
quality of bowel habits not parasympatholytic drugs support/severe mucous or obstruction, fistula or
requiring medication/rectal (e.g., Lomotil)/mucous blood discharge necessitating perforation; GI bleeding
discomfort not requiring discharge not sanitary pads/abdominal requiring transfusion;
analgesics necessitating sanitary distention (flat plate abdominal pain or
pads/rectal or abdominal radiograph demonstrates tenesmus requiring tube
pain requiring analgesics distended bowel loops) decompression or bowel
diversion
Lung No change Mild symptoms of dry cough or Persistent cough requiring Severe cough unresponsive to Severe respiratory
dyspnea on exertion narcotic, antitussive narcotic antitussive agent or insufficiency/continuous
agentsldyspnea with dyspnea at rest/clinical or oxygen or assisted
minimal effort but not at radiological evidence of acute ventilation
rest pneumonitis/intermittent
oxygen or steroids may be
required
Genitourinary No change Frequency of urination or nocturia Frequency of urination or Frequency with urgency and Hematuria requiring
twice pretreatment habit/dysuria, nocturia that is less nocturia hourly or more transfusion/acute bladder
urgency not requiring frequent than every hour. frequently/dysuria, pelvis obstruction not
medication Dysuria, urgency, bladder pain or bladder spasm secondary to clot
spasm requiring local requiring regular, frequent passage, ulceration, or
anesthetic (e.g., narcotic/gross hematuria with/ necrosis
Pyridium) without clot passage
c; Heart No change over Asymptomatic but objective Symptomatic with EKG Congestive heart failure, angina Congestive heart failure,
t? baseline evidence of EKG changes or changes and radiological pectoris, pericardial disease angina pectoris,
pericardial abnormalities findings of congestive responding to therapy pericardial disease,
without evidence of other heart heart failure or arrhythmias not
disease pericardial disease/no responsive to
specific treatment nonsurgical measures
required
CNS No change Fully functional status (i.e., able to Neurological findings Neurological findings requiring Serious neurological
work) with minor neurological present sufficient to hospitalization for initial impairment that includes
findings, no medication needed require home care/ management paralysis, coma, or
nursing assistance may seizures > 3 per week
be required/medications despite medication/
including steroids/ hospitalization required
antiseizure agents may be
required
Hematologic WBC (X 1000) => 4.0 3.0-< 4.0 2.0-< 3.0 l.O-< 2.0 < 1.0
Platelets ( X 1000) > 100 75-< 100 so-< 75 25-< 50 < 25 or spontaneous
bleeding
Neutrophils (X 1000) => 1.9 1.5-< 1.9 l.O-< 1.5 0.5-< 1.0 < 0.5 or sepsis
Hemoglobin (GM %) > 11 11-9.5 < 9.5-7.5 < 7.5-5.0 -
Hematocrit (%) => 32 28-c 32 < 28 Packed cell transfusion required -

Guidelines: The acute morbidity criteria are used to score/grade tocity from radiation therapy. The criteria are relevant from day 1, the commencement of therapy, through day 90.
Thereafter, the EORTURTOG Criteria of Late Effects are to be utilized.
The evaluator must attempt to discriminate between disease and treatment related signs and symptoms.
An accurate baseline evaluation prior to commencement of therapy is necessary.
All toxicities Grade 3, 4 or 5* must be verified by the Principal Investigator.
* Any toxicity which caused death is Graded 5.
 Table 2. RTOG/EORTC late radiation morbidity scoring scheme

Organ Tissue 0 Grade 1 Grade 2 Grade 3 Grade 4 5

Skin None Slight atrophy; pigmentation change; Patch atrophy; moderate Market atrophy; gross telangiectasia Ulceration
some hair loss telangiectasia; total hair loss
Subcutaneous None Slight induration (fibrosis) and loss Moderate fibrosis but Severe induration and loss of Necrosis
z tissue or subcutaneous fat asymptomatic; slight field subcutaneous tissue; field
% contracture; < 10% linear contracture > 10% linear D
reduction measurement E
Mucous None Slight atrophy and dryness Moderate atrophy and Marked atrophy with complete Ulceration A
membrane telangiectasia; little mucous dryness T
Severe telangiectasia H
Salivary None Slight dryness of mouth; good Moderate dryness of mouth; poor Complete dryness of mouth; no Fibrosis
glands response on stimulation response on stimulation response on stimulation
Spinal cord None Mild L’Hermitte’s syndrome Severe L’Hermitte’s syndrome Objective neurological findings at Mono, para quadraplegia
or below cord level treated
Brain None Mild headache; slight lethargy Moderate headache Severe headaches; severe CNS Seizures or paralysis
Great lethargy dysfunction (partial loss of power Coma
or dyskinesia)
Eye None Asymptomatic cataract Symptomatic cataract Severe keratitis; severe retinopathy PanopthalmitisJBlindness
Minor cornea1 ulceration or keratitis Moderate comeal ulceration; minor or detachment
retinopathy or glaucoma Severe glaucoma
Larynx None Hoarseness; slight arytenoid edema Moderate arytenoid edema; Severe edema; severe chondritis Necrosis
chondritis
Lung None Asymptomatic or mild symptoms Moderate symptomatic fibrosis or Severe symptomatic fibrosis or Severe respiratory
(dry cough) pneumonitis (severe cough) pneumonitis insufficiency/Continuous 02/
Slight radiographic appearances Low grade fever; patchy Dense radiographic changes Assisted ventilation
radiographic appearances
Heart None Asymptomatic or mild symptoms; Moderate angina on effort Severe angina; pericardial effusion; Tamponade/Severe heart
transient T wave inversion & ST Mild pericarditis; normal heart size; constrictive pericarditis; moderate failure/Severe constrictive
changes; sinus tachychardia > persistent abnormal T wave and heart failure; cardiac pericarditis T
110 (at rest) ST changes; low ORS enlargement; EKG abnormalities 0
Esophagus None Mild fibrosis; slight difficulty in Unable to take solid food normally; Severe fibrosis; able to swallow Necrosis/Perforation Fistula
swallowing solids; no pain on swallowing semisolid food; only liquids; may have pain on R
swallowing dilatation may be indicated swallowing; dilatation required A
Small/Large None Mild diarrhea; mild cramping; bowel Moderate diarrhea and colic; bowel Obstruction or bleeding, requiring Necrosis/Perforation Fistula D
intestine movement 5 times daily; slight movement > 5 times daily; surgery I
rectal discharge or bleeding excessive rectal mucus or A
intermittent bleeding T
Liver None Mild lassitude; nausea, dyspepsia; Moderate symptoms; some Disabling hepatitic insufficiency; Necrosis/Hepatic coma or I
slightly abnormal liver function abnormal liver function tests; liver function tests grossly encephalopathy 0
serum albumin normal abnormal; low albumin; edema or N
ascites
Kidney None Transient albuminuria; no Persistent moderate albuminuria Severe albuminuria; severe Malignant hypertension L
hypertension; mild impairment of (2+); mild hypertension; no hypertension; persistent anemia Uremic coma A
renal function; urea 25-35 mg %; related anemia; moderate (< 10 g %); severe renal failure; Urea > 100% T
creatinine 1.5-2.0 mg %; impairment of renal function urea > 60 mg %; creatine > 4.0 E
creatinine clearance > 75% Urea > 36-60 mg %; creatinine mg %; creatinine clearance <
clearance (50-74%) 50% E
Bladder None Slight epithelial atrophy; minor Moderate frequency; generalized 3qp.l.y- p icy & dysuria; severe Necrosis/Contracted bladder F
telangiectasia (microscopic telangiectasia; intermittent . :langiectasia (often (capacity < 100 cc) F
hematuria) macroscopic hematuria ,Iuae); frequent Severe hemorrhagic cystitis E
hematuria; reduction in bladder C
capacity (< 150 cc) T
Bone None Asymptomatic; no growth Moderate pain or .:I#.-l-:;ess; Severe pain or tenderness; complete Necrosis/Spontaneous fracture S
retardation; reduced bone density growth retardation; irregular bone arrest of bone growth: dense
sclerosis bone sclerosis
Joint None Mild joint stiffness; slight limitation Moderate stiffness; intermittent or Severe joint stiffness; pain with Necrosis/Complete fixation
of movement moderate joint pain; moderate severe limitation of movement
limitation of movement
1346 I. J. Radiation Oncology 0 Biology 0 Physics
of reactions is graded from 1 through 4. In most RTOG
publications, “major’ ’ toxicities have been reported as
Grades 3,4, and 5 taken together. Grade 4 and 5 toxicities
have been presented in detail. Cumulative probabilities
of “major” or Grade 4 and 5 toxicities are presented as
risk estimates at discrete intervals, such 1 year, 2 year,
etc. More often the probabilities are presentedgraphically
to show the propensity for continued increaseswith time.
Late radiation morbidity criteria differ substantially
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2. Cox, J. D., ed. Moss’ Radiation Oncology: Rationale,
Volume 3 I, Number 5, 1995
from those of other modalities. Long periods of observa-
tion are required to assesseffects of radiation therapy
alone or combined with surgical resection, cytotoxic
drugs, and hormones.
Late effects of radiations on normal tissues may in-
crease with time and it is conceivable that interventions
could lessen the risk or severity of these effects. Early
predictors and more quantitative measuresof severity are
desirable.
techniques, results, 7th ed. St. Louis:C. V. Mosby Co.;
1994.
3. Stone, R. S. Neutron therapy and specific ionization. AJR
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